Document Detail


Synergistic induction of matrix metalloproteinase 1 by interleukin-1alpha and oncostatin M in human chondrocytes involves signal transducer and activator of transcription and activator protein 1 transcription factors via a novel mechanism.
MedLine Citation:
PMID:  11665970     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To investigate the mechanism of interleukin-1alpha (IL-1alpha) and oncostatin M (OSM) synergistic regulation of matrix metalloproteinase 1 (MMP-1) in human chondrocytes. METHODS: Using an immortalized human chondrocyte cell line (T/C28a4), we investigated regulation of the MMP-1 gene. Northern blotting and flow cytometric analysis were used to assess changes in receptor, MMP-1, and c-fos expression. Transient transfections using MMP-1 promoter/luciferase constructs, electrophoretic mobility shift assay, and site-directed mutagenesis were used to investigate MMP-1 promoter activation. RESULTS: We found no alteration in the expression of receptors used by these cytokines after stimulation with IL-1alpha/OSM. Using MMP-1 promoter/luciferase reporter constructs, we found that the proximal (-517/+63) region of the MMP-1 promoter was sufficient to support a synergistic activation. A role for activated signal transducers and activators of transcription (STAT-3) was demonstrated, although no binding of STAT-3 to the MMP-1 promoter was found. However, constitutive binding of activator protein 1 (AP-1) was detected, and changes in c-fos expression could modulate promoter activity. CONCLUSION: Since no changes in receptor expression were observed, receptor modulation cannot account for the IL-1alpha/OSM synergy observed. Instead, the interplay of various intracellular signaling pathways is a more likely explanation. STAT activation is required, but STAT proteins do not interact directly with the MMP-1 promoter. We propose that activated STATs stimulate c-fos expression, and changes in expression of the AP-1 components regulate MMP-1 expression. We highlight a new mechanism for MMP-1 regulation in human chondrocytes that could provide potential new therapeutic targets.
Authors:
J B Catterall; S Carrère; P J Koshy; B A Degnan; W D Shingleton; C E Brinckerhoff; J Rutter; T E Cawston; A D Rowan
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  44     ISSN:  0004-3591     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2001 Oct 
Date Detail:
Created Date:  2001-10-22     Completed Date:  2001-12-04     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2296-310     Citation Subset:  AIM; IM    
Affiliation:
Department of Rheumatology, School of Clinical Medical Sciences, The Medical School, University of Newcastle upon Tyne, UK. J.B.Catterall@ncl.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Cell Line, Transformed
Chondrocytes / physiology*
DNA-Binding Proteins / physiology
Drug Synergism
Humans
Interleukin-1 / pharmacology*
Matrix Metalloproteinase 1 / physiology*
Oncostatin M
Peptides / pharmacology*
Proto-Oncogene Proteins c-fos / physiology
STAT3 Transcription Factor
Signal Transduction / drug effects
Trans-Activators / physiology
Transcription Factor AP-1 / physiology
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Interleukin-1; 0/OSM protein, human; 0/Peptides; 0/Proto-Oncogene Proteins c-fos; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/Trans-Activators; 0/Transcription Factor AP-1; 106956-32-5/Oncostatin M; EC 3.4.24.7/Matrix Metalloproteinase 1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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